Lacosamide-induced sinus node dysfunction followed by severe agranulocytosis.

BACKGROUND: Lacosamide (LCM) is the antiepileptic drug approved by the U.S. Food and Drug Administration in 2008 that facilitates slow activation of the voltage-gated sodium channels. Neutropenia and cardiac events including sinus node dysfunction (SND) and atrioventricular block have been previously reported as adverse effects of LCM. To date, there have been no reports of severe agranulocytosis resulting in death associated with LCM. Additionally, there have been no reports of concomitant SND and agranulocytosis after LCM administration. Herein we report the first case of LCM-induced severe SND followed by agranulocytosis. CASE PRESENTATION: The patient with focal epilepsy was initiated on LCM 100 mg/day and the dose was increased to 200 mg/day on the 9th hospital day. Severe SND developed on the 10th hospital day and LCM was discontinued. Thereafter agranulocytosis appeared on the 11th hospital day, and the patient died from septic shock on the 15th hospital day. CONCLUSIONS: This case illustrates the need for careful follow-up of the electrocardiogram and the complete blood cell counts when initiating LCM. Moreover, it should be noticed that various side effects may occur simultaneously in the early period of LCM use, even for a short time and at low dosages.

TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling.

Sinoatrial node fibrosis is involved in the pathogenesis of sinus sick syndrome (SSS). Transient receptor potential (TRP) subfamily M member 7 (TRPM7) is implicated in cardiac fibrosis. However, the mechanisms underlying the regulation of sinoatrial node (SAN) fibrosis in SSS by TRPM7 remain unknown. The aim of this study was to investigate the role of angiotensin II (Ang II)/TRPM7/Smad pathway in the SAN fibrosis in rats with SSS. The rat SSS model was established with sodium hydroxide pinpoint pressing permeation. Forty-eight rats were randomly divided into six groups: normal control (ctrl), sham operation (sham), postoperative 1-, 2-, 3-, and 4-week SSS, respectively. The tissue explant culture method was used to culture cardiac fibroblasts (CFs) from rat SAN tissues. TRPM7 siRNA or encoding plasmids were used to knock down or overexpress TRPM7. Collagen (Col) distribution in SAN and atria was assessed using PASM-Masson staining. Ang II, Col I, and Col III levels in serum and tissues or in CFs were determined by ELISA. TRPM7, smad2 and p-smad2 levels were evaluated by real-time PCR, and/or western blot and immunohistochemistry. SAN and atria in rats of the SSS groups had more fibers and higher levels of Ang II, Col I and III than the sham rats. Similar findings were obtained for TRPM7 and pSmad2 expression. In vitro, Ang II promoted CFs collagen synthesis in a dose-dependent manner, and potentiated TRPM7 and p-Smad2 expression. TRPM7 depletion inhibited Ang II-induced p-Smad2 expression and collagen synthesis in CFs, whereas increased TRPM7 expression did the opposite. SAN fibrosis is regulated by the Ang II/TRPM7/Smad pathway in SSS, indicating that TRPM7 is a potential target for SAN fibrosis therapy in SSS.

Sinus node dysfunction: an adverse effect of lacosamide.

Lacosamide, a recently introduced antiepileptic drug, acts by enhancing the slow inactivation of voltage-dependent sodium channels. Cardiac conduction disturbances, namely atrial fibrillation and atrioventricular block, have been reported in patients with epilepsy. We report a patient with drug-resistant focal epilepsy who developed asymptomatic sinus node dysfunction following lacosamide use, which resolved on stopping lacosamide. This is the first report of sinus node dysfunction associated with lacosamide therapy.

[Sick sinus syndrome possibly due to lopinavir-ritonavir: report of two cases].

We describe herein two cases of sick sinus syndrome possibly due to lopinavir-ritonavir in HIV-infected individuals. The heart rate dropped to 30 to 40 beats per minute in both cases, but patients remained asymptomatic and recovered promptly after discontinuation of lopinavir-ritonavir. The time until onset varied; one patient developed bradyarrhythmia 9 days after the initial dose, and another 4 hours after. Since lopinavir-ritonavir is a frequently used antiretroviral agent, clinicians must be aware of this potentially lethal adverse effect.

Sinus Node Dysfunction Co-occurring with Immune Checkpoint Inhibitor-associated Myocarditis.

Immune checkpoint inhibitor (ICI)-induced myocarditis is a potentially life-threatening adverse event. We herein report a rare case of sick sinus syndrome (SSS) co-occurring with ICI-associated myocarditis. A 71-year-old woman with lung cancer undergoing pembrolizumab monotherapy was admitted owing to a fever, worsening kidney function, and sinus bradycardia. She was diagnosed with multi-organ immune-related adverse events, including myocarditis. Pulse steroid therapy was initiated immediately under the support of a temporary pacemaker, which resulted in the resolution of SSS in a few days. Biopsy specimens of the endomyocardium showed active myocarditis. Thus, we should be aware that SSS can co-occur with ICI-induced myocarditis.

Lithium-induced sinus node dysfunction at therapeutic serum levels.

Lithium-induced cardiotoxicity, though rare at therapeutic levels, has been reported frequently in overdoses. We report a patient who developed sinus bradycardia while being treated with lithium carbonate even though the serum lithium levels were within the therapeutic range. It reversed following withdrawal of lithium and did not reappear with subsequent treatment with valproate.

[Cilostazol and sick sinus syndrome]. / Efecto del cilostazol en la enfermedad del nodo sinusal.

Here we present the case of a 60-year-old patient with sinus node disease (NSS), symptomatic with dizziness and angor. The electrocardiogram showed episodes of sinus pauses with nodal escapes. During hospitalization, pending the placement of a definitive pacemaker, cilostazol (100 mg every 12 hours orally) was indicated, observing an increase in heart rate 48 hours after starting the medication, and the disappearance of sinus pauses in the 24 hours Holter. Our objective has been to show that cilostazol can be useful in patients with SNN, although long-term chronotropic effects of this treatment has yet to be evaluated.

Se presenta el caso de una paciente de 60 años con enfermedad del nodo sinusal (ENS), sintomática con mareos y ángor, con electrocardiograma que evidenciaba episodios de pausas sinusales con escapes nodales. Durante la internación, a la espera de colocación de marcapaso definitivo, se indicó cilostazol (100 mg cada 12 h vía oral), observando a las 48 horas del inicio un incremento en la frecuencia cardíaca y la desaparición de las pausas sinusales en Holter de 24 horas. Nue stro objetivo ha sido demostrar que el cilostazol puede ser útil en pacientes con ENS, aunque es necesario evaluar los efectos cronotrópicos a largo plazo de este tratamiento.

Sinus node dysfunction in ATX-II-induced in-vitro murine model of long QT3 syndrome and rescue effect of ranolazine.

The aim of this study was to characterize the role of the late Na+ current (I(Na,L)) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, I(Na,L). In sixteen hearts studied, exposure to 1-10nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early after depolarisations, delayed after depolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n=5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 microM ranolazine in intact hearts (n=11) and isolated sino-atrial preparations (n=5). In conclusion, the I(Na,L) enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the I(Na,L) blocker, ranolazine (10 microM). The results suggest that I(Na,L) blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.

Sinus node dysfunction in association with chronic lithium therapy: a case report and review of literature.

Lithium is derived from the Greek word "lithia" which means "stone." Since its discovery by the Swedish chemist Arfedsson in the year 1817, it has been used for treatment of gout, hypertension, uremia, and rheumatism. Currently, lithium is the treatment of choice for the long-term control of mania and to prevent relapse in bipolar disorder. It has a narrow therapeutic index (0.6-1.2 mEq/L). Lithium overdose has been associated with a wide range of cardiovascular complications including cardiac arrhythmias and interstitial myocarditis. We present a review of published cases relevant to lithium-related cardiotoxicity.

Two methods for modeling of sick sinus syndrome in rats: Ischemia reperfusion and sodium hydroxide induced injury.

The Sick Sinus Syndrome (SSS) is a serious life-threatening heart disease. It is important to establish a credible and stable sinus node damage model. In this study, we use two methods to construct an SSS damage model in rats. One is to inject sodium hydroxide to the SSS area through internal jugular vein. Another is to cause ischemia-reperfusion injury on the SSS area. 43 healthy SD rats were randomly divided into 4 groups, namely ischemia-reperfusion injury group (IRIG), inject sodium hydroxide group (ISHG), and propranolol group (PG) and the control group (CG). The achievement ratio of modeling was 67% in the IRIG and 83% in the ISHG. The HR significantly decreased after operation in the IRIG and ISHG compared with pre-operation (P＜0.01). The HR was reduced by above 30% in these 2 groups after modeling, while the reduction was better maintained in IRIG. Additionally, the sinoatrial node recovery time (SNRT) and sinoatrial conduction time (SACT) were significantly prolonged compared with pre-modeling in 2 groups (P < 0.01). Morphology results showed blurry in structure and boundaries with pale cytoplasm. It is speculated that IRIG and ISHG modeling might influence the calcium concentration and damage the sinus node function by decrease the expression of HCN4 and SCN5A, which impaired the driving ability of sinus node and leading to apoptosis. Ischemia reperfusion injury and sodium hydroxide injury could construct stable SSS models which could represent clinic pathological damage. Thus, both methods could be used for further studies of the SSS mechanisms and drugs.

Bradycardia in a Man With Hypertension.

A man without cardiac symptoms was found to have a slow irregular pulse, and an electrocardiogram revealed sinus bradycardia with escape-capture bigeminy. He was taking verapamil, clonidine, and hydralazine for hypertension. The verapamil was discontinued; he returned to normal sinus rhythm and was discharged on the second hospital day.

Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice.

Aims: Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice. Methods and results: Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8 weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Conclusions: Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.

[Case of west syndrome associated with transient marked sinus dysfunction during ACTH therapy].

An 11-month-old boy with multiple congenital anomalies developed West syndrome and ACTH therapy was started. Marked bradycardia during sleep was observed after the 16th day of ACTH therapy. Echocardiography revealed both intraventricular septum and left ventricular free wall thickening with preservation of biventricular function. Both the patient's marked sinus dysfunction and his cardiac hypertrophy were suspected to be related to the ACTH therapy. Sinus function gradually improved after ACTH therapy was withdrawn and treatment with oral beta-agonist was started. We believe that the patient's sinus dysfunction and cardiac hypertrophy were caused by ACTH treatment because of the subacute nature of the onset and the absence of other potentially contributory factors such as infection or respiratory failure. Pediatricians should be aware that cardiac dysfunction could be associated with ACTH therapy for West syndrome.

Sick sinus syndrome associated with anti-programmed cell death-1.

BACKGROUND: Use of anti-programmed cell death-1 (anti-PD-1) has been successful in treating many types of cancers. Despite its promising efficacy, immune-related adverse events are still a major concern. Immune-related cardiotoxicity, which is rare but fatal, has recently become a focus of attention. Cardiotoxicities including myocarditis, cardiomyopathy, cardiac fibrosis, heart block and cardiac arrest have been reported. Of these toxicities, myocarditis is often accompanied by dysrhythmia. The presentation of sick sinus syndrome as an immune-related adverse event has not yet been reported. Here, we reported the first case of sick sinus syndrome, a rare toxicity induced by anti-PD-1. CASE PRESENTATION: A 42-year-old male patient who had metastatic hepatocellular carcinoma failed treatment with sorafenib. Pembrolizumab at a fixed dose of 100 mg every three weeks was given. His heart rate gradually slowed down and he presented sick sinus syndrome with a lowest heart rate of 38 bpm after six cycles of pembrolizumab. He denied chest tightness, cold sweating, palpitation and dyspnea. Lab data including cardiac enzyme, electrolytes and thyroid function were all within a normal range. Simultaneously, he complained of fatigue, dizziness and anorexia with hypotension. Lab data revealed low cortisol and ACTH levels. Anti-PD-1 induced adrenal insufficiency was suspected. Low-dose cortisone (12.5 mg) was prescribed, and the patient's symptoms, hypotension and sick sinus syndrome showed rapid improvement. Cortisone was gradually titrated and discontinued three weeks later. His sick sinus syndrome did not relapse and the cortisol and ACTH level returned to normal. CONCLUSIONS: Sick sinus syndrome caused by anti-PD-1 treatment is a rare adverse event. With the development of sick sinus syndrome, myocarditis should be the first differential diagnosis because of its lethality. From this case, we learned that sick sinus syndrome may be a presentation of immune- or adrenal insufficiency-mediated sinus node dysfunction, both could be reversed with a glucocorticoid supplement.

Lithium-induced sinus node disease at therapeutic concentrations: linking lithium-induced blockade of sodium channels to impaired pacemaker activity.

The present report describes a case of sinus node arrest in a manic-depressive patient being treated with lithium carbonate with a therapeutic serum level of lithium. A permanent rate-modulated ventricular pacemaker was inserted and lithium therapy was continued. A review of literature revealed several other similar case reports in which both therapeutic and toxic levels of serum lithium levels were associated with sinus node dysfunction and bradyarrhythmias. Because lithium is a potent blocker of cardiac sodium channels, and given the critical importance of sodium channels in pacemaker activity, lithium-induced sodium channel blockade is likely an important mechanism in sinus node dysfunction.

[Transient sick sinus syndrome by oral intake of high dose dehydrocodeine for postherpetic neuralgia].

An 88-year-old man was admitted to the intensive care unit after the ingestion of 150 mg of dehydrocodeine. The ECG showed severe brodycardia and he was diagnosed as sick sinus syndrome. The recovering of sinus node function took 5 days after the ingestion. The complication observed suggests that transient hypoxia induced by ingestion of high dose DHC had affected sinus node.

Transient sick sinus syndrome with complete atrioventricular block associated with ergonovine intake: A case report.

RATIONALE: More mature or older women are more likely to undergo in vitro fertilization and embryo implant. These women have a greater chance of receiving ergonovine therapy because of a suspected abortion. We present this case report to call attention to a latent lethal adverse effect in everyday obstetric practice using ergonovine. It requires more attention and close monitoring PATIENT CONCERNS:: We presented the case of a 38-year-old female patient with general weakness and mild chest tightness after ergonovine use. DIAGNOSES: She was diagnosed as transient sick sinus syndrome and complete atrioventricular block with junctional escape rhythm after diagnostic work up. INTERVENTIONS: Conservative treatment with discontinuation of ergonovine and bed rest. OUTCOMES: Her sinus rhythm returned to normal the day after ergonovine was discontinued. The patient remained symptom-free since recovery of her sinus rhythm. LESSONS: Ergonovine may cause symptomatic and lethal bradyarrhythmia. Withdrawal of the causative medication and adequate supportive care can lead to a favorable outcome in these patients. More related cases should be reported. Further evaluation for treatment and prognosis are necessary.